Destruction of CD4+ T cells is considered the primary cause of immunodeficiency manifested by opportunistic infections in HIV-1-infected humans as well as in SIV-infected macaques. Subsequently, HIV/SIV-associated chronic immune activation also has emerged as an important explanation for HIV pathogenesis. Although a clearly-defined mechanism about the cause of this general immune activation has yet to be demonstrated, a microbial translocation theory has been proposed whereby breakdown of the mucosal barrier and mucosal immunity is thought to occur after with depletion of CD4 T cells resulting in systemic exposure to mucosal microbial pathogens and their products (e.g. endotoxin). The cause and effect of this theory of pathogenesis, however, has yet to be elucidated, especially since not all infected individuals with low CD4 T cell levels progress similarly to AIDS. The purpose of this proposal is to examine earlier stages of HIV/SIV-associated pathogenesis that could account for microbial translocation by focusing on the role of macrophages. Macrophages are important components of the innate immune system, link the transition from innate to adaptive immunity, and serve as host cell targets of HIV/SIV infection. In support of the rationale to focus on macrophages in this proposal, our recent data showed a high monocyte turnover in SIV-infected animals compared to control uninfected animals that directly correlated with progression to AIDS. Massive destruction of tissue macrophages observed in the lymph nodes of an infected monkey appeared to contribute to a high monocyte turnover rate. Furthermore, preliminary data indicated that a specific cell subset of recently differentiated macrophages from monocytes were the main target of SIV infection. The main goal of the proposed application is to address the role of tissue macrophages in the pathogenesis of AIDS using the non-human primate model of SIV infection. The goal of this proposal is to determine if microbial translocation leading to systemic immune activation is due to faltering innate immunity by dysfunctional macrophages. The hypothesis is that damage to specific macrophage cell subsets by SIV infection will compromise the first line of defense in innate immunity, and as a consequence, the bacterial flora of the digestive tract will break through the mucosal barrier to contribute to systemic immune activation and pathogenesis of AIDS.